23 March 2022

EU GMP Annex 1 Manufacture of sterile medicinal products

EU GMP Annex 1 Manufacture of sterile medicinal products revision to be released mid-year 

The Annex 1 of the EU GMP Guide “Manufacture of Sterile Medicinal Products” is considered the most important European regulatory standard for the manufacture of sterile pharmaceutical products. The pending and long-awaited Annex 1 revision covering good manufacturing practice (GMP) for sterile drug products is planned to be issued in mid-year 2022. A working group consisting of regulators from EMA, PIC/S and WHO endorsed a revised version in mid-February and the document now being reviewed by EU legal services as well as by PIC/S and WHO.

Revised Annex 1 will bring a significant improvements, is much more comprehensive than current version and emphasizes the importance of risk management in preventing microbiological contamination of products.  The new version consists of 57 pages, with a revised chapter layout, compared to the current version with 16 pages. The revision has 10 sections covering scope, principles, pharmaceutical quality system (PQS), premises, equipment, utilities, personnel, production, and specific technologies, environmental and process monitoring and quality controls. The document builds on the pharmaceutical quality system requirements (QMS) detailed in Chapter 1 of the EU GMP guide and helps ensure that an effective quality risk management is integrated into all areas of the product life cycle, with the aim to minimize microbial contamination and ensure the quality of sterile products that are manufactured. 

What’s new:

  • a content on barrier technologies designed to prevent contamination, such as restricted access barrier systems (RABS) and isolators to address the ambiguities of the previous guidelines;
  • the revision aligns with the European Pharmacopoeia (EP) in the water for injection (WFI) section by allowing distillation or an equivalent purification process, such as reverse osmosis when coupled with other appropriate techniques;
  • new draft focuses on removing operators from production line processes to reduce the risk of contamination. The implementation of smart factory technology (SFT) could be one means to achieve this;
  • a content on closed systems and single-use systems used for aseptic processing.

The revised Annex 1 retains the controversial provision calling for testing filters in the cleanroom and a provision calling for testing filters used in the sterilization process, called pre-use, post-sterilization integrity testing (PUPSIT). However, there is a new change exempting radiopharmaceutical manufacturers from performing PUPSIT testing.

The new Annex 1 draft serves as a detailed roadmap for the requirements pharma companies in the EU must follow to remain compliant. Rather than wait for Annex 1 to be published, manufacturers of sterile medicinal products should take a proactive approach to future compliance. By spending time and resources on new technologies and processes now, manufacturers could avoid a last-minute rush to meet the new rules. There are also plans underway to develop an aide memoire to ensure the document is implemented in a harmonized way.